New Cobalt-mediated Methods for the Synthesis of Bioactive Triterpenoid Natural Products

The development of new, concise, and modular approaches toward physiologically important natural products that are synthetically flexible and amenable to late-stage modification is important for accessing new lead compounds and novel structural motifs for investigation as therapeutics to treat human disease. Provided that from 1981-2020 roughly 65% of all FDA approved drugs were influenced by natural products research, the unique molecular scaffolds found in nature are excellent starting points for the discovery of new lead therapeutics. While there are many factors to consider when developing a lead compound, structural complexity has become an increasingly important factor for clinical success in recent years. This work will advance new operationally-simple catalytic protocols employing bench-stable cobalt(III) complexes to build synthetically useful motifs through carbon-carbon bond formation reactions including carbonyl additions and allylboration reactions that are high utility for the synthesis of biologically relevant natural products, agrochemicals, and pharmaceuticals. The methods advanced in this work will contribute fundamental knowledge on the reactivity of first-row transition metal catalysts to help facilitate their use in new, cost-effective, and safer chemical processes. The utility and enabling power of the protocols developed with cobalt(III)-based catalysts in this work will be demonstrated through applications in the total synthesis biologically relevant triterpenoid natural products. This will lead to the first total synthesis of the sodwanones A-C and sodwanone H, which exhibits 2 nM nanomolar activity against A549 lung cancer cell lines and has the potential to serve as a lead compound for further biochemical investigations. The newly prepared compounds have a high potential to serve as a new class of antibiotics and sporicidal agents against C. difficile providing a new treatment for this common hospital acquired infection, thereby having a direct impact in solving an unmet challenge in healthcare. The pursuit of these aims will provide and expand research and training opportunities for 8 undergraduate students and one graduate student at Old Dominion University. Student trainees will develop important skillsets through cross-training in synthetic method development, total synthesis, organometallic chemistry, computational chemistry, medicinal chemistry, and biochemistry. Project Number: 1R15GM163256-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Kyle Lambert | Institution: OLD DOMINION UNIVERSITY, NORFOLK, VA | Award Amount: $580,064 | Activity Code: R15 | Study Section: Chemical Synthesis and Biosynthesis Study Section[CSB] View on NIH RePORTER: https://reporter.nih.gov/project-details/11292244